Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors.
Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors.
复制标题
DOI：
10.1038/onc.2013.242
复制
发表时间：
2014-05-29
期刊：
影响因子：
8
通讯作者：
Chaudhary PM
中科院分区：
文献类型：
--
作者：
Tolani B;Gopalakrishnan R;Punj V;Matta H;Chaudhary PM
原发性渗出性淋巴瘤(PEL)是一种侵袭性非霍奇金B细胞淋巴瘤，与Kaposi肉瘤相关疱疹病毒(KSHV)感染相关。(+)-JQ1和I-BET151是最近发现的两种新的BET溴结构域染色质相关蛋白的小分子抑制剂，它们在癌症中显示出令人印象深刻的临床前活性，在癌症中，由于染色体易位使MYC基因处于超级增强子的控制下，MYC在转录水平上过表达。相比之下，PEL细胞缺乏myc基因的结构变化，但由于KSHV编码的潜伏蛋白的活性，Myc蛋白被解除了调控。我们报道，PEL细胞系对BET溴域抑制剂诱导的生长抑制高度敏感，在用这些药物处理后，经历了G0/G1细胞周期停滞、细胞凋亡和细胞衰老，但没有诱导裂解重新激活。用BET抑制剂处理PEL细胞系可抑制MYC的表达，并导致依赖于MYC的基因在全基因组范围内发生扰动。沉默BRD4和MYC的表达阻止了细胞的增殖和细胞周期的进展，而来自逆转录病毒启动子的MYC的异位表达拯救了(+)-JQ1诱导的细胞生长停滞。在PEL异种移植模型中，(+)-JQ1显著抑制肿瘤生长并提高存活率。综上所述，我们的结果表明，BET抑制剂的用途可能不仅限于基因组改变导致MYC极高表达的癌症，它们对MYC基因组位点结构完整且c-Myc蛋白在翻译后水平解除调控且仅适度过度表达的癌症可能具有同等或更高的活性。
Primary effusion lymphoma (PEL) is an aggressive form of non-Hodgkin's B cell lymphoma associated with infection by Kaposi's sarcoma associated herpesvirus (KSHV). (+)-JQ1 and I-BET151 are two recently described novel small molecule inhibitors of BET bromodomain chromatin-associated proteins that have shown impressive preclinical activity in cancers in which MYC is over-expressed at the transcriptional level due to chromosomal translocations that bring the MYC gene under the control of a super-enhancer. PEL cells, in contrast, lack structural alterations in the MYC gene, but have deregulated Myc protein due to the activity of KSHV-encoded latent proteins. We report that PEL cell lines are highly sensitive to BET bromodomain inhibitors-induced growth inhibition and undergo G0/G1 cell-cycle arrest, apoptosis and cellular senescence, but without the induction of lytic reactivation, upon treatment with these drugs. Treatment of PEL cell lines with BET inhibitors suppressed the expression of MYC and resulted in a genome-wide perturbation of MYC-dependent genes. Silencing of BRD4 and MYC expression blocked cell proliferation and cell-cycle progression, while ectopic expression of MYC from a retroviral promoter rescued cells from (+)-JQ1-induced growth arrest. In a xenograft model of PEL, (+)-JQ1 significantly reduced tumor growth and improved survival. Taken collectively, our results demonstrate that the utility of BET inhibitors may not be limited to cancers in which genomic alterations result in extremely high expression of MYC and they may have equal or perhaps greater activity against cancers in which the MYC genomic locus is structurally intact and c-Myc protein is deregulated at the post-translational level and is only modestly over-expressed.